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Abstract

Objective: To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)–related dyskinesia and genotype–phenotype relationship.

Methods: We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases.

Results: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation.

Conclusions:ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis.

GLOSSARY

ADCY5=

adenylate cyclase 5;

ATP=

adenosine-5′-triphosphate;

cAMP=

3′,5′-cyclic adenosine monophosphate;

ChDys=

chorea-dystonia;

EHC=

essential hereditary chorea;

FDFM=

familial dyskinesia with facial myokymia;

MIP=

molecular inversion probe;

SNP=

single nucleotide polymorphism;

STRP=

short tandem repeat marker

Footnotes

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